De novo CACNA1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism.

Pflügers Archiv : European journal of physiology
Nadine J OrtnerJörg Striessnig

Abstract

The identification of rare disease-causing variants in humans by large-scale next-generation sequencing (NGS) studies has also provided us with new insights into the pathophysiological role of de novo missense variants in the CACNA1D gene that encodes the pore-forming α1-subunit of voltage-gated Cav1.3 L-type Ca2+ channels. These CACNA1D variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca2+ influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic CACNA1D variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca2+ channel blockers as a potential therapeutic option.

References

Apr 18, 2003·Proceedings of the National Academy of Sciences of the United States of America·Matteo E MangoniJoël Nargeot
May 18, 2004·The Journal of Clinical Investigation·Martina J Sinnegger-BraunsJörg Striessnig
May 3, 2005·Proceedings of the National Academy of Sciences of the United States of America·Igor SplawskiMark T Keating
Sep 15, 2005·The Journal of Biological Chemistry·Annette HohausSteffen Hering
Nov 26, 2008·Molecular Pharmacology·Martina J Sinnegger-BraunsJörg Striessnig
Jul 15, 2009·Neurobiology of Learning and Memory·Brandon C McKinneyGeoffrey G Murphy
Aug 12, 2009·The International Journal of Neuropsychopharmacology·Perrine BusquetNicolas Singewald
Nov 17, 2009·Pflügers Archiv : European journal of physiology·Ping Liao, Tuck Wah Soong
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andrea MarcantoniEmilio Carbone
Feb 17, 2010·The Journal of Physiology·Stephen C Cannon
Mar 6, 2010·Pflügers Archiv : European journal of physiology·Daniela Pietrobon
Mar 10, 2010·Pflügers Archiv : European journal of physiology·Jörg StriessnigAlexandra Koschak
Dec 17, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Thomas P GiordanoAnjali M Rajadhyaksha
Jun 3, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jan J HirtzEckhard Friauf
Sep 24, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Kathryn SchierberlAnjali M Rajadhyaksha
Oct 15, 2011·The Journal of Biological Chemistry·Gabriella BockAlexandra Koschak
May 1, 2012·Neuron·Ivan IossifovMichael Wigler
Jun 6, 2012·Molecular Psychiatry·A S LeeAnjali M Rajadhyaksha
Jun 16, 2012·Frontiers in Pharmacology·Karin Jurkat-RottFrank Lehmann-Horn
Oct 2, 2012·Biochimica Et Biophysica Acta·Diane LipscombeSummer E Allen
Oct 19, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jan J HirtzEckhard Friauf
Aug 6, 2013·Nature Genetics·Elena A B AzizanMorris J Brown
May 29, 2014·Hypertension·Fabio Luiz Fernandes-RosaMaria-Christina Zennaro
Aug 26, 2014·The Journal of Steroid Biochemistry and Molecular Biology·Saulo J A FelizolaHironobu Sasano
Dec 24, 2014·Nature·UNKNOWN Deciphering Developmental Disorders Study
Jan 27, 2015·Biological Psychiatry·Alexandra PinggeraJörg Striessnig
Mar 6, 2015·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Sue RichardsUNKNOWN ACMG Laboratory Quality Assurance Committee
May 15, 2015·Current Molecular Pharmacology·David H F VandaelEmilio Carbone
May 20, 2015·Current Molecular Pharmacology·Matthew J BetzenhauserCharles Antzelevitch
Aug 5, 2015·Proceedings of the National Academy of Sciences of the United States of America·Koshiro NishimotoWilliam E Rainey

❮ Previous
Next ❯

Methods Mentioned

BETA
cesarean section

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Hereditary Sensory Autonomic Neuropathy

Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Landau-Kleffner Syndrome

Landau Kleffner syndrome (LKS), also called infantile acquired aphasia, acquired epileptic aphasia, or aphasia with convulsive disorder, is a rare childhood neurological syndrome characterized by the sudden or gradual development of aphasia (the inability to understand or express language) and an abnormal electroencephalogram. Discover the latest research on LKS here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Regulation of Vocal-Motor Plasticity

Dopaminergic projections to the basal ganglia and nucleus accumbens shape the learning and plasticity of motivated behaviors across species including the regulation of vocal-motor plasticity and performance in songbirds. Discover the latest research on the regulation of vocal-motor plasticity here.